Pharmaceutical compositions for relief of dysmenorrhea and/or premenstrual syndrome and process

ABSTRACT

A pharmaceutical composition for relieving symptoms of dysmenorrhea and/or premenstrual syndrome comprising a combination of ibuprofen and hydrochlorothiazide, and, optionally, an antihistamine.

This is a continuation-in-part application of U.S. Ser. No. 907,698filed Sept. 15, 1986, now U.S. Pat. No. 4,888,343 issued Dec. 19, 1989.

FIELD OF INVENTION

This invention relates to pharamaceutical compositions useful in thetreatment of dysmenorrhea and/or premenstrual syndrome.

BACKGROUND OF INVENTION

Dysmenorrhea is a term used to describe painful menstruation. The painmay range from minor cramping to intense pain accompanied by diarrhea,nausea and vomiting, with sensations of pelvic heaviness and breastfullness. Premenstrual syndrome refers to the tension accruing prior tothe onset of menstruation, and is characterized by headaches,nervousness and edema. Once menstruation has begun, there is noticeablepolyuria and rapid disappearance of the edema.

Pharmaceutical products for the treatment of dysmenorrhea and/orpremenstrual syndrome are known in the prior art and have been marketedcommercially. Thus, for example, a number of commercially availableproducts contain a combination of acetaminophen and pamabrom or acombination of acetaminophen, pamabrom and pyrilamine maleate. Productsof this character do not contain a non-steroidal anti-inflammatoryagent, such as ibuprofen or aspirin, which are highly important but notoptimal in relieving the symptoms of dysmenorrhea and/or premenstrualsyndrome. The acetaminophen used in such products is known to be aneffective analgesic but is not generally recognized as exhibitingsignificant anti-inflammatory properties.

There is at least one commercial product containing a non-steroidalanti-inflammatory such as aspirin that is marketed for use in treatingdysmenorrhea and/or premenstrual syndrome. Disadvantageously, thisproduct does not contain a reliably effective diuretic which, whencombined with an effective NSAID, provides relief of the array ofsymptoms of dysmenorrhea and/or premenstrual syndrome. Thus, thisproduct contains a mixture of aspirin, cinnamedrine and caffeine.Cinnamedrine is conventionally recognized as an antispasmodic. Caffeine,although it is recognized as a diuretic, is not a highly potentdiuretic. Moreover, the latter has the disadvantage of inducingsleeplessness in the subjects to whom it is administered, an importantconsideration for evening utility.

Compositions for use in the treatment of dysmenorrhea, which aredisclosed in European Patent Application 0 081 823, are "combinations ofanalgesics (including prostaglandin synthetase inhibitors such aspirin,indomethacin and ibuprofen), diuretics, antihistamines andantispasmadics." The invention of this European Patent Application issaid to reside in also incorporating 5-500 mg dextromethorphanhydrochloride with one or more of: a conventional diuretic such asammonium chloride, pamabrom and hydrochlorothiazide; a conventionalantihistaminic such as pyrilamine maleate; a conventional antispasmodic,for example, cinnamedrine, or a conventional analgesic such as, forexample, aspirin, acetaminophen, indomethacin, ibuprofen or naproxen.

G. F. Shah et al, Effect of Nonsteroidal Antiinflammatory Drugs (NSAIDS)on Diuretic Property of Hydrochlorothiazide, Indian J. Pharm., 17:224-8(1985), studied the effects of several NSAIDs including ibuprofen onhydrochlorothiazide (HCTZ) induced changes in urinary volume, sodium,potassium and creatinine excretion, in conscious rats. Shah et alconcluded that the diuretic effect as well as the increased urinarysodium and potassium excretion elicited by HCTZ at 2.5 and 5 mg/kg wereinhibited after oral administration of NSAIDs such as indomethacin,oxyphenbutazone, ibuprofen and naproxen, in doses which inhibited therat carrageenin induced hind paw oedema.

Shah et al reports that of the NSAIDs tested, ibuprofen was found to bethe most potent in antagonizing diuretic and natriuretic activity. Thus,a dose of 12.5 mg/kg ibuprofen inhibited the diuretic activity of 5mg/kg HCTZ, while 25 mg/kg ibuprofen significantly antagonized thediuretic activity of 10 mg/kg HCTZ. It is further seen from Table 4 ofShah et al that as the ratio of ibuprofen to HCTZ increased at aconstant dose of HCTZ, there was a concomitant reduction in the diureticactivity. For example, at 10 mg/kg HCTZ, the reported diuretic activityis 2.2±0.16, while at 10 mg/kg HCTZ and 25 mg/kg ibuprofen, the diureticactivity was 1.6±0.07, a reduction of about 28%. Similarly, Shah et alobserved like reductions in natriuretic activity.

It is noteworthy that Shah et al administered each of the ibuprofen andthe HCTZ in a gum arabic suspension. As pointed out in Bowman & Rand,Textbook of Pharmacology, p. 40.10 (2nd Edition 1980), the activity ofHCTZ is preparation-dependent. Accordingly, Shah et al's observationsare not predictive of the performance of a tablet comprising ibuprofenand HCTZ.

SUMMARY OF THE INVENTION

The present invention involves a composition which contains as the onlypharmaceutically active ingredients (a) a non-steroidalanti-inflammatory selected from the group consisting of aspirin andibuprofen, (b) a diuretic selected from the group consisting of pamabromand hydrochlorothiazide, and, optionally, (c) an antihistamine,preferably pyrilamine or a pharmaceutically acceptable salt thereof,these ingredients being present at a level in these compositions toafford relief from the symptoms of dysmenorrhea and/or premenstrualsyndrome when said compositions are administered to subjects exhibitingthese conditions. Pyrilamine has been shown to be a safe and effectivecalmative, relieving the tension of dysmenorrhea and/or premenstrualsyndrome. The compositions of the present invention advantageouslycontain an effective anti-inflammatory agent, a reliably effectivediuretic, and, optionally, an effective calmative.

DETAILED DESCRIPTION OF THE INVENTION

The non-steroidal anti-inflammatory agents useful in the compositionsherein disclosed are ibuprofen or aspirin. Combinations of these drugsmay also be employed but ordinarily either one or the other will beutilized. The quantity of said anti-inflammatory agent contained in thepresent composition may be expressed in the form of the daily averagedose for this agent, which will vary with anti-inflammatory drugselected. Generally for ibuprofen this will be about 100 to about 2,000mg/day with the preferred range being about 200 to about 1,200 mg/day.In the case of aspirin the general average daily dose will be about 200mg/day to about 5 gm/day, the preferred range being about 500 to about2000 mg/day.

In similar fashion, the quantity of the particular diuretics of use inthe present invention and contained in the present products may also beexpressed on the basis of the daily average dose for the diuretics (i.e.pamabrom, hydrochlorothiazide or combination thereof), which also willvary with the particular diuretic selected. When the diuretic ishydrochlorothiazide the general average daily dose for this drugprovided by the product will be from about 5 to about 250 mg/day and inthe case of pamabrom from about 5 to about 500 mg/day. In both cases thepreferred range is about 25 to about 200 mg/day.

When the antihistamine (i.e. pyrilamine or its pharmaceuticallyacceptable salts) is employed in the practice of this invention itslevel of use is also expressible on the basis of its daily average dose.In this case, the daily average dose will be from about 15 mg to about400 mg. However, the preferred daily average dose for the antihistaminewill fall in the range of from about 30 mg to about 200 mg.

Any of the pharmaceutically acceptable salts of pyrilamine may beutilized in carrying forward the purpose of this invention. By way ofexample mention may be made of pyrilamine maleate citrate, hydrochlorideor sulfate.

The products of this invention will generally be administered in aconvenient unit dosage form, preferably in solid dose form such as atablet, powder, capsule, and the like. The quantity of the respectiveingredients that may be contained in this unit dosage form is given inthe table below:

    ______________________________________                                                Unit Dosage Form                                                              General Range in mg                                                                        Preferred Range in mg                                    ______________________________________                                        Ibuprofen 50 mg to 800 mg                                                                              100 mg to 400 mg                                     Aspirin   50 mg to 975 mg                                                                              150 mg to 650 mg                                     Pamabrom   1 mg to 100 mg                                                                               5 mg to 50 mg                                       Hydrochloro-                                                                             1 mg to 50 mg  5 mg to 25 mg                                       thiazide                                                                      Pyrilamine Salt                                                                          0 mg to 100 mg                                                                               15 mg to 50 mg                                      ______________________________________                                    

Optimally each unit dosage form will contain from about 200 mg to about400 mg of ibuprofen or from about 325 to 500 mg of aspirin.

The prior art Shah et al article demonstrates significantly antagonizeddiuretic activity of HCTZ when administered in the presence of ibuprofenat ibuprofen/HCTZ ratios of 0.625:1 to 10:1. Surprisingly andunexpectedly, it has been found by Applicants that the diuretic activityantagonism did not worsen as anticipated at higher ratios of ibuprofento HCTZ, as demonstrated hereinafter with regard to Examples 8 and 9. Inthe compositions of the present invention, the ratio of ibuprofen toHCTZ is above about 16:1, preferably from about 16:1 to 64:1, mostpreferably from about 24:1 to 48:1.

In addition to the pharmacologically active ingredients mentioned above,the products of this invention may also contain other excipients. Theseto a large extent will depend on the nature of the unit dosage formselected for dispensing the present composition.

The present products may be made into capsules, tablets, powders,caplets and may be film coated, enteric coated or formulated intosustained release dosage forms or liquid dosage compositions. Whenformed into tablets or caplets they may contain adjuvants thatfacilitate the tableting of the product or enhance its elegance ordissolution rates. Generally illustrative of the adjuvants that may becontained in the various dosage forms encompassed in the presentinvention are: disintegrating agents, binders, lubricants, fillers,glidents, surfactants, flavoring agents, sweeteners, solvents, liquidcarriers, suspending agents, preservatives, etc. More particularly theadjuvants that may be contained in the various dosage forms over andabove the active ingredients are as follows:

Caplet and Tablet: Cellulose, lactose, corn starch, stearic acid, water,gelatin, talc, Sterotex, magnesium stearate, terra alba, sucrose,Cab-0-Sil, acacia, etc.

Capsule: spray dried lactose, dimethylsiloxane, corn starch, magnesiumstearate, sucrose, Cab-o-Sil, etc.

Liquid Dosage Forms: polyethylene glycol, sucrose, Povidone, sodiumcitrate, citric acid, flavor, color, quinine, water, etc.

Sustained release compositions may contain such things as glycerylmonostearate, glyceryl distearate, cellulose ethers such ashydroxypropyl methylcellulose and hydroxy propylcellulose, stearic acid,etc.

In general, the products of the present invention may be prepared usingthe standard technique well known to those skilled in this art, e.g.,standard tableting or capsule preparing procedures. However, whenpamabrom is utilized as the diuretic and ibuprofen as the non-steroidalanti-inflammatory it has been found advantageous to granulate thepamabrom before mixing it with the ibuprofen. These ingredients, whenmixed together in standard procedures, tend to form eutectic mixtureswith the result that tablets containing such a mixture become soft uponexposure to stress testing conditions and capsules turned pasty. Inaddition both of these dosage forms also changed color from white toyellow or orange when prepared using the standard procedures.

When an antihistamine, e.g., pyrilamine maleate, is used in conjunctionwith the pamabrom and ibuprofen, it is often advantageous to granulatethe combination of pamabrom and antihistamine before mixing thiscombination with the ibuprofen. This mixture, with or without otheradjuvants may then be used to prepare the dosage forms, e.g., capsule,tablets.

The products of this invention may be administered using a variety ofregimens. Ordinarily the acceptable daily dose will be provided bytaking the product twice, three times or four times a day.

The following examples are given to further illustrate the presentinvention. It is to be understood, however, that the invention is notlimited thereto.

The following are the chemical definitions of the materials used in theExamples and identified therein by their trade designations:

Avicel PH 101 and 102: Microcrystalline Cellulose, FMC Inc.

Starch 1500: Pregelatinized starch, Colorcon Inc., West Point, Pa.

Silicone Oil: Dimethicone (U.S.P.), Dimethylpolysiloxane 350 CS, DowCorning

Tween 80: Polysorbate 80 (CTFA-Cosmetic Ingredient Dictionary, ThirdEdition, p. 247)

Cab-0-Sil: Fumed Silica, Cabot, Inc.

Povidone: Polyvinyl pyrrolidone, GAF Corp.

Crospovidone XLlO: Cross linked Polyvinylpyrrolidone, GAF Corp.

The "Ibuprofen Granulation" used in Examples 5 and 6 below is preparedby first mixing ibuprofen (200 mg) and corn starch (50 mg). An aqueousgranulating solution, prepared containing Povidone K29-32 (6 mg), AvicelPH 101 (41.5 mg) and Crospovidone XL-10 (1.5 mg), was used to granulatethe ibuprofen/starch mixture.

EXAMPLE 1

    ______________________________________                                        Ibuprofen/Pamabrom/Pyrilamine Maleate: Capsules                               Formula CE 3375-70                                                            Ingredients      Amount Per Dose                                              ______________________________________                                        a.     Ibuprofen     150.00 mg                                                b.     Pamabrom      25.00 mg                                                 c.     Pyrilamine Maleate                                                                          15.00 mg                                                 d.     Avicel pH 101 50.00 mg                                                 e.     Starch 1500   117.50 mg                                                f.     Silicon Oil    2.00 mg                                                 g.     Tween 80       0.50 mg                                                 h.     Cab-O-Sil      0.25 mg                                                                      360.25 mg                                                ______________________________________                                         Method                                                                        A. Blend b, d and 30 mg e                                                     B. Dissolve c in water and use to granulate A, then dry                       C. Blend 87.5 mg e, f and g                                                   D. Blend B, C, a and h. Fill into size #1 capsules                       

EXAMPLE 2

    ______________________________________                                        Ibuprofen/Pamabrom: Capsules                                                  Formula CS 3570-05                                                            Ingredients     Amount Per Dose                                               ______________________________________                                        a.      Ibuprofen   150.00 mg                                                 b.      Pamabrom    25.00 mg                                                  c.      Avicel pH 101                                                                             82.50 mg                                                  d.      Starch 1500 90.00 mg                                                  e.      Silicon Oil  2.00 mg                                                  f.      Tween 80     0.50 mg                                                                      350.00 mg                                                 ______________________________________                                         Method:                                                                       A. Mix b, 50 mg d and 42.5 mg c, granulate with water and dry                 B. Mix 40 mg d, e and f                                                       C. Mix A, B, a and 40 mg c                                                    D. Fill C into size #1 capsules                                          

EXAMPLES 3 AND 4

    ______________________________________                                        Ibuprofen/Hydrochlorothiazide HCl: Capsule                                                Example 3     Example 4                                                       Formula CS 3570-14                                                                          Formula CS 3570-31                                  Ingredients Amount Per Dose                                                                             Amount Per Dose                                     ______________________________________                                        a.  Ibuprofen   200.00 mg     300.00 mg                                       b.  Hydrochloro-                                                                               12.50 mg      12.50 mg                                           thiazide HCl                                                              c.  Starch 1500 134.50 mg     183.50 mg                                       d.  Silicon Oil  2.00 mg       2.80 mg                                        e.  Tween 80     0.50 mg       0.70 mg                                        f.  Cab-O-Sil    0.50 mg       0.50 mg                                                        350.00 mg     500.00 mg                                       ______________________________________                                         Method:                                                                       A. Blend all ingredients                                                      B. Fill blends for CS357014 into size #1 capsules and for CS357031 into       size #0 capsules.                                                        

EXAMPLE 5

    ______________________________________                                        Ibuprofen/Pamabrom/Pyrilamine Maleate Tablets                                                       Formula CS 3570-34                                      Ingredients           Amount Per Dose                                         ______________________________________                                        a.    Pamabrom            25.00 mg                                            b.    Pyrilamine Maleate  15.00 mg                                            c.    Starch 1500         75.00 mg                                            d.    Povidone, USP (K29-32)                                                                            0.75 mg                                             e.    Hydroxypropyl methylcellulose                                                                     4.11 mg                                                   E5-Premium                                                              f.    Propylene Glycol    0.90 mg                                             g.    Ibuprofen Granulation                                                                             224.24 mg                                                 (Equivalent to 150 mg                                                         Ibuprofen)                                                              h.    Silicon Oil         2.00 mg                                             i.    Tween 80            0.50 mg                                             j.    Starch 1500         35.00 mg                                                                      382.50 mg                                           ______________________________________                                         Method:                                                                       A. Blend a, b and c, granulate with water and dry                             B. Dissolve d, e and f in water and use to spray coat A                       C. Blend h, i and j                                                           D. Blend B, C and g and compress into tablet                             

EXAMPLE 6

    ______________________________________                                        Ibuprofen/Pamabrom/Pyrilamine Maleate Tablets                                                       Formula CS 3570-32                                      Ingredients           Amount Per Dose                                         ______________________________________                                        a.    Pamabrom            25.00 mg                                            b.    Pyrilamine Maleate  15.00 mg                                            c.    Avicel PH 101       50.00 mg                                            d.    Povidone, USP (K29-32)                                                                            6.74 mg                                             e.    Hydroxypropyl methylcellulose                                                                     6.63 mg                                                   E5-Premium                                                              f.    Propylene Glycol    1.24 mg                                             g.    Ibuprofen Granulation                                                                             224.24 mg                                                 (Equivalent to 150 mg                                                         Ibuprofen)                                                              h.    Starch 1500         35.00 mg                                            i.    Silicone Oil        2.00 mg                                             j.    Tween 80            0.50 mg                                                                       366.35 mg                                           ______________________________________                                         Method                                                                        A. Blend a, b and c                                                           B. Dissolve 5.6 mg d in water and use to granulate A, then dry                C. Dissolve 1.14 mg d, e and f in water and use to spray coat B               D. Blend h, i and j                                                           E. Blend C, D and g and compress into tablet                             

EXAMPLE 7

    ______________________________________                                        Ibuprofen/Hydrochlorothiazide HCl Tablets                                                          Formula CS 3570-15                                       Ingredients          Amount Per Dose                                          ______________________________________                                        a.    Ibuprofen          200.00 mg                                            b.    Corn Starch NF     50.00 mg                                             c.    Povidone, K29-32   6.00 mg                                              d.    Avicel PH 101      41.50 mg                                             e.    Avicel PH 102      136.50 mg                                            f.    Hydrochlorothiazide HCl, USP                                                                     12.50 mg                                             g.    Crospovidone XL10  2.50 mg                                              h.    Cab-O-Sil          0.50 mg                                              i.    Magnesium Stearate 0.50 mg                                                                       450.00 mg                                            ______________________________________                                         Method:                                                                       A. Blend all ingredients geometrically                                        B. Compress into tablets                                                 

EXAMPLE 8

A preclinical diuretic efficacy study was conducted in two stages(Experiments A and B), the experiments being run fifteen days apart andeach experiment lasting two days.

In Experiment A, five doses of hydrochlorothiazide (HCTZ) ranging from0.25 to 4 mg/kg were tested, while in Experiment B, four doses of HCTZranging from 1.5 to 12 mg/kg were used and coadministered with aconstant dose of 96 mg/kg ibuprofen.

Also tested in Experiment A was a control containing no actives (vehicleonly), and also tested in Experiment B was a first control containing noactives and a second control containing 96 mg/kg ibuprofen.

Ten male Wistar rats were used per dose in each experiment. The ratswere fasted overnight prior to testing and during testing. After thestudy dose (or vehicle) was administered, each animal was given ahydrating dose of normal saline (30 ml/kg). Each rat was placed in anindividual cage and urine collected for five hours. Total urinaryvolume, total urinary sodium and potassium excretion, and urinary pHwere determined, which parameters were analyzed as ml/kg body weight,mEq/kg body weight, and pH, respectively.

The results of the tests are provided below.

    ______________________________________                                                   Volume Na        K                                                            (ml/kg)                                                                              (mEq/kg)  (mEq/kg)  pH                                      ______________________________________                                        Experiment A                                                                  HCTZ                                                                          (mg/kg)                                                                        0           18.69    2.53      0.73    5.72                                   0.25        23.17    3.47      0.80    5.78                                   0.50        22.01    3.33      0.95    5.76                                   1.0         28.61    4.09      0.97    5.61                                   2.0         32.91    5.20      1.16    5.26                                   4.0         37.04    5.29      1.58    5.64                                  Experiment B                                                                  HCTZ (mg/kg) w/96                                                             mg/kg Ibuprofen                                                                0 w/o Ibuprofen                                                                           20.24    2.93      0.80    6.11                                   0 w/Ibuprofen                                                                             12.61    1.49      0.55    6.22                                   1.5         22.98    3.57      1.19    6.06                                   3.0         17.08    2.92      0.99    5.98                                   6.0         22.97    3.66      1.08    5.75                                  12.0         26.37    4.42      1.22    6.05                                  ______________________________________                                    

The urinary excretion data from Experiment A demonstrate a clear-cutdose response for HCTZ. The data collected for the two controls (--O--mg HCTZ w/o ibuprofen and --O-- mg HCTZ w/ibuprofen) in Experiment Billustrate the extent to which ibuprofen itself causes urinaryconcentration. The data reflect urinary excretion of sodium andpotassium, and reduced volume. Unexpectedly, when combined withibuprofen, the diuretic efficacy of HCTZ is exhibited as increasedurinary volume, as well as the content of sodium and potassium. In Shahet al, a significant inhibition of diuresis was observed at the 5:1ibuprofen/HCTZ ratio. To the contrary, in these studies above theantidiuretic efficacy of ibuprofen was significantly offset at ratios ofibuprofen to HCTZ of 16:1 to 64:1.

EXAMPLE 9

A single blind, randomized, four-treatment, four-period crossover studyof ibuprofen and hydrochlorothiazide (HCTZ) interaction was conductedwith 16 female human adults. The study medications were: (a) a placebo,(b) 12.5 mg HCTZ, (c) 400 mg ibuprofen, and (d) in combination, 400 mgibuprofen and 12.5 mg HCTZ (32:1 ibuprofen/HCTZ ratio).

Alcohol consumption was not permitted for 48 hours before dosing;caffeine was restricted for 24 hours before dosing. The test subjectswere held to a controlled diet with fluid intake, sodium and potassiumrestricted.

Urine was collected and pooled for 24 hours prior to each drug, and wascollected voluntarily from the test subjects at 1, 2, 3, 4, 5, 6, 9, 12,15 and 24 hours post treatment.

The 6- and 24-hour urinary excretion data is reported below.

    ______________________________________                                                     Urine      Na        K                                                        Volume     Excretion Excretion                                   Medication   (ml)       (mEq)     (mEq)                                       ______________________________________                                        Cumulative 6-Hour Urinary Excretion                                           (a) Placebo       935        44     14.2                                      (b) 12.5 mg HCTZ 1405        98     19.3                                      (c) 400 mg Ibuprofen                                                                            799        29     11.9                                      (d) 400 mg Ibuprofen                                                                           1165        76     17.7                                          12.5 mg HCTZ                                                              Cumulative 24-Hour Urinary Excretion                                          (a) Placebo      2172       157     45.0                                      (b) 12.5 mg HCTZ 2681       193     45.5                                      (c) 400 mg Ibuprofen                                                                           2078       138     39.5                                      (d) 400 mg Ibuprofen                                                                           2641       190     43.5                                          12.5 mg HCTZ                                                              ______________________________________                                    

Shah et al observed approximately a 25% decrease in diuretic activity atibuprofen/HCTZ ratios of 5:1 and 10:1. Given a typical dose response,one of ordinary skill in the art would anticipate logically thatinhibition of urinary activity would be greater as the ibuprofen/HCTZratio increased. Unexpectedly, the data above demonstrate that theanticipated dose response does not occur. Thus, at the end of the 6-hourperiod, the suppression in urine volume was only 17%. After 24 hours theurine output of those test subjects taking the ibuprofen/HCTZ medicationwas essentially no different from those taking HCTZ only----up about 23%compared to placebo. Those test subjects taking ibuprofen alone had asuppression in urine output of 12% as compared to placebo over the24-hour period. Similarly, after 24 hours the sodium excretion level forthe ibuprofen/HCTZ dosing is about the same as for HCTZ alone, whileibuprofen alone had a 34% decrease, all as compared to the placebo.

Extrapolation of the data in Shah et al would suggest total inhibitionof HCTZ-induced natriuresis at the 32:1 ibuprofen/HCTZ ratio.Unexpectedly, this was clearly not the case in the clinical studiesreported on above. Moreover, the excretion of Na⁺ without concomitantequivalent loss of K⁺ as observed herein provides a safety advantage forthe ibuprofen/HCTZ combination reported on above.

What is claimed is:
 1. A pharmaceutical composition for the relief ofdysmenorrhea and/or premenstrual syndrome in humans containing in unitdose form essentially the only pharmacologically active ingredientsabout 50 to about 800 mg ibuprofen and about 1 to about 50 mg ofhydrochlorothiazide, said pharmaceutically active ingredients beingpresent in said composition in amounts sufficient to afford relief fromthe symptoms of dysmenorrhea and/or premenstrual syndrome with theibuprofen/hydrochlorothiazide weight ratio being from about 16:1 toabout 64:1, said composition further containing an antihistamine at anantihistaminicly calmative effective level.
 2. The composition of claim1 wherein the unit dosage form contains from about 100 to about 400 mgibuprofen and from about 5 to about 25 mg hydrochlorothiazide.
 3. Thecomposition of claim 1 or 2 wherein the ibuprofen/hydrochlorothiazideratio is from about 24:1 to about 48:1.
 4. The composition of claim 1 or2 wherein the unit dosage form contains from about 15 to about 50 mgantihistamine.
 5. The composition of claim 4 wherein theibuprofen/hydrochlorothiazide ratio is from about 24:1 to about 48:1. 6.The composition of claim 5 wherein said antihistamine is pyrilaminemaleate.
 7. The composition of claim 4 wherein said antihistamine ispyrilamine maleate.
 8. The composition of claim 1 or 2 wherein theibuprofen/hydrochlorothiazide ratio is about 32:1.
 9. The composition ofclaim 7 wherein the ibuprofen/hydrochlorothiazide ratio is 32:1.
 10. Thecomposition of claim 1 or 2, including a pharmaceutical carrier.
 11. Aprocess for relieving symptoms of dysmenorrhea and/or premenstrualsyndrome in a human subject exhibiting such symptoms comprisingadministering to said subject a composition of claim 1 in an amountsufficient to relieve said symptoms.
 12. The process of claim 11 whereinthe unit dose form is administered one to six times daily.
 13. Theprocess of claim 12 wherein the ibuprofin/hydrochlorothiazide ratio inthe composition is from about 24:1 to about 48:1.
 14. The process ofclaim 1 wherein the unit dose form is administered two to four timesdaily.
 15. The process of claim 14 wherein theibuprofen/hydrochlorothiazide ratio is 32:1.